Childhood respiratory diseases and their pathophysiologic antecedents are important clinical and public[unreadable] health problems that have both environmental and genetic determinants. Although progress has been made[unreadable] in identifying the genes and exposures related to asthma occurrence, respiratory symptoms and lung[unreadable] function, more research is needed to understand the role of genetics in susceptibility and identify critical[unreadable] pathways and vulnerable populations for interventions. This project proposes to investigate the contribution[unreadable] of genetic variation in inflammatory responses during childhood to 1) the occurrence of common respiratory[unreadable] diseases. 2) inter-individual differences in lung function growth, and 3) susceptibility for adverse respiratory[unreadable] effects of ambient air pollutants. The proposed program of research builds on the rich health, exposure and[unreadable] genetic data resources of the Children's Health Study (CHS), an ongoing cohort study investigating both[unreadable] genetic and environmental factors related to children's respiratory disease in over 11,000 southern California[unreadable] children. We will assess the broad hypotheses that inter-related pathways involved in inflammatory[unreadable] responses (innate, adaptive systems) and oxidative/nitrosative stress 1) are determinants of childhood[unreadable] asthma and lung function development, and 2) modulate susceptibility to ambient respirable particles (PM[0.25],[unreadable] PM[0.25-2.50, and PM[2.5-10] characteristics, constituents), ozone and nitrogen dioxide. We propose to conduct a[unreadable] pathways-driven candidate gene-environment association study to examine the relationships between[unreadable] outcomes (asthma incidence, respiratory symptoms), lung function growth and 273 key genes in key[unreadable] inflammatory pathways. To characterize the genetic contribution of each locus, tagging SNPs will be[unreadable] selected including conserved SNPs or SNPS with coding or regulatory functions. Children in the CHS[unreadable] (n=7700) would be genotyped for 6,000 SNPs across the 273 genes and each genetic locus tested for[unreadable] associations with each phenotype. Tests of a subset of gene-environment and gene-gene interactions would[unreadable] be conducted based on genetic main effects and a priori hypotheses-based pathway topologies. Our[unreadable] approach that employs genotype-based coefficient of ancestry, emerging analytic methods for global and[unreadable] specific tests of association, and novel methods to include prior biological knowledge of disease[unreadable] pathophysiology is complementary to discovery approaches such as whole genome association studies. The[unreadable] CHS offers a unique resource to assess the effects of genetic variation in critical pathways on children's[unreadable] respiratory health. The size, substantial genotype data, high levels of exposure and longitudinal health data[unreadable] make the project proposed in this application feasible, cost-effective and timely. The results will guide future[unreadable] mechanistic studies and intervention strategies for primary and secondary prevention of asthma and chronic[unreadable] obstructive respiratory diseases.[unreadable]